Vorasidenib May ‘Change the Treatment Paradigm’ for Low-Grade Glioma

Patients with grade 2 IDH-mutant glioma (a type of brain cancer) experienced a 61% reduced risk of progression or desk when treated with vorasidenib (AG-881) compared with placebo, according to results from the phase 3 INDIGO clinical trial, presented at the 2023 ASCO Annual Meeting and published in the New England Journal of Medicine.

Progression-free survival (time from treatment until disease progression) with vorasidenib was 27.7 months compared with 11.1 months for those treated with placebo. Treatment in the study was given during a “watch and wait” period used to delay the start of debilitating chemoradiation therapy, which is standard following glioma resection. In addition to improvements in progression-free survival, vorasidenib also resulted in a significant lengthening in the interval to receipt of another treatment.

“Our study shows that targeting IDH mutations with vorasidenib significantly delays tumor growth and the need for more toxic therapies,” lead author Dr. Ingo Mellinghoff, of Memorial Sloan Kettering Cancer Center, said in a statement. “This is clinically meaningful because patients diagnosed with grade 2 glioma with IDH mutations are typically young, otherwise healthy individuals. The results of this trial offer a chance to change the treatment paradigm for this type of glioma and could bring the first new targeted therapy for low-grade glioma.”

In the study, 331 patients were randomly assigned to receive oral vorasidenib (168 patients) at 40 mg once daily or matched placebo (163 patients) in 28-day cycles.

Histologic subtypes of low-grade glioma were evenly distributed between oligodendroglioma and astrocytoma. The location of the tumor at primary diagnosis was frontal for two-thirds of patients. The longest diameter of tumor was 2 or more centimeters for most patients (82.7% vs 84.0%, for vorasidenib and placebo, respectively). The median interval from last glioma surgery to randomization was 2.4 years and 21.5% had received 2 or more tumor surgeries before enrollment.

All patients were positive for an IDH mutation, with the majority having an IDH1 alteration, which was present in 97% of those in the vorasidenib arm and for 93.3% in the placebo group. More than half of patients also had a codeletion in chromosome 1p/19q.

The median follow-up was 14 months for vorasidenib and was 14.3 months for placebo. Progression occurred in 28% of those in the vorasidenib arm compared with 54% for those in the placebo group. Investigator-assessed results were similar to those reported in the primary analysis, with vorasidenib remaining superior.

There was an 85.6% likelihood of not requiring another intervention at 18 months in the vorasidenib arm compared with 47.4% in the placebo arm. At the 24-month assessment, 83.4% of patients in the vorasidenib arm still had not required another intervention compared with 27% in the placebo group. Following initial results, the study was unblinded and patients were allowed to cross over. There were 52 patients initially in the placebo arm (31.9%) who crossed over to receive vorasidenib.

“Second interim analysis was so clear and showed efficacy so clearly that the data monitoring board recommended that we unblind,” Mellinghoff noted.

The 18-month progression-free survival rate was 60.4% in the vorasidenib group compared with 26.7% in the placebo group. The 24-month progression-free survival rates were 50.7% in the vorasidenib arm compared with 17.6% in the placebo group.

The objective response rate (percentage of patients whose disease shrunk as a result of treatment) was 10.7% with vorasidenib compared with 2.5% for placebo. In the vorasidenib group, this included two partial responses (1.2%) and 16 minor responses (9.5%). The placebo arm was all minor responses. Most patients had stable disease, with progressive disease seen in 6.0% and 8.6% of those in the vorasidenib and placebo arms, respectively.

An ASCO Expert commenting on the results, Dr. Glenn Lesser, said “These results are quite striking and they’re statistically highly significant, and more important, they’re clinically very important. In select patients with low-grade glioma, we can potentially delay the use of these toxic chemotherapy and radiation for years, perhaps many years, and delay the toxicity.”

Side effects of any grade occurred in 94.6% of those in the vorasidenib group and for 93.3% of those in the placebo group. Grade 3 or higher (moderate to severe) side effects occurred in 22.8% of patients in the vorasidenib arm compared with 13.5% of those in the placebo arm. The most common side effects in the vorasidenib arm were related to liver enzyme increases, including increases in alanine aminotransferase (ALT; 38.9%; 9.6% was grade 3 or higher), aspartate aminotransferase (AST; 28.7%; 4.2%), and gamma-glutamyl transferase (GGT; 15.6%; 3.0%).

There were 3 serious side effects reported in the vorasidenib arm that were reported to be associated with the treatment, specifically ALT increase, liver failure and hepatitis. All serious side effects were considered resolved at the time of the analysis in September 2022. Side effects led to discontinuation for 3.6% of patients in the vorasidenib arm compared with 1.2% in the placebo arm. Dose reductions were needed for 10.8% of those in the vorasidenib arm compared with 3.1% in the placebo group. Dose interruptions occurred for approximately one-quarter of patients in both arms.

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